It is already known to provide formulations containing NSAIDs in the form of gels, creams and sprays intended for topical application for regional delivery to underlying tissues, for the relief of pain and inflammation and to restore mobility. However, some NSAIDs exhibit undesirable side effects either on their own or in interaction with other drugs and, for this reason, there is a continuing need to provide a topical formulation which provides an effective amount for therapeutic activity at the regional tissue target below the application site while at the same time preventing general uptake in the systemic circulation. The objective is to provide local efficacy without the potential for systemic adverse consequences such as gastric, hepatic, renal and other effects. The efficacy of known topical formulations does not compare favourably with that of orally-administered compositions which, however, have general uptake in the systemic circulation.
Many NSAID drugs have been formulated for topical-regional delivery including salicylates, indomethacin, piroxicam, ketoprofen, diclofenac and others. Effective topical therapy, whether for local dermal, regional or transdermal therapeutic purposes, requires the achievement of therapeutic drug concentrations at the target site and depends among other things on drug potency and the extent of skin penetration. For topical regional purposes, diclofenac, ketorolac and ketoprofen are preferred; in particular, the efficacy index for diclofenac (the ratio of its skin penetration to potency) is greater than that for piroxicam by a factor in the order of 103 demonstrating the importance of correct drug selection. Diclofenac and ketoprofen are particularly preferred on the basis of their more rapid systemic clearance compared with other drugs. Overall, diclofenac is generally considered to be the preferred NSAID for topical regional application. Trials of a 1% diclofenac sodium gel for use in treating ostheoarthritis have demonstrated efficacy and safety, although other diclofenac formulations show efficacy which is inferior to that derived from oral therapy. One currently-available formulation is marketed as “Voltarol Emulgel P”, containing 1.16% of diclofenac diethyl ammonium, equivalent to 1 g of diclofenac sodium per 100 g of gel.
In terms of achieving optimum benefit to risk ratio following topical application, it is appropriate to consider the rate of individual drug metabolism in the skin (where rapid metabolism would reduce the potential for local efficacy) and clearance from the systemic circulation (where slow clearance would tend to result in therapeutic levels building up in plasma), which factors vary considerably between different drugs. It has been found from in vivo human studies that topical application of a 4% diclofenac sodium gel achieves skin concentrations which are 2-3 times higher than a therapeutic oral dose of 15 mg diclofenac taken 3 times daily for 3 days, despite having a plasma concentration lowered by approximately 60 times.
Certain currently-available formulations of diclofenac salts are based on the use of a non-volatile solvent such as propylene glycol in combination with a volatile solvent such as ethanol or isopropanol or mixtures thereof. The purpose of the volatile solvent is to increase solubility and also to lead to volume reduction on evaporation in use and thus an increase in diclofenac concentration in the non-volatile, residual phase. Supersaturation of the diclofenac salts in the residual phase may occur but, in any event, it is the degree of saturation in the residual phase which drives the percutaneous penetration process, since diffusion is more a function of chemical potential rather than absolute diclofenac concentration. By way of example, the saturated solubility of diclofenac acid in polyethylene glycol is 11.18% w/w, whereas in propylene glycol the saturated solubility is only 1.16% w/w. Despite this, there is no significant difference between diclofenac flux from these respective systems and indeed, because the saturated solubility of the sodium salt of diclofenac acid in propylene glycol is approximately 50% w/w, it is very difficult to achieve saturation, more especially supersaturation, unless either extremely high concentrations of the salt are used, or an extremely low percentage of the residual phase solvent is used. The pH of the formulation may also have an effect on solubility such that lower pH values, for example pH 3.5 to 5.5, decrease solubility of the diclofenac and thus enhance the flux or activity state of the diclofenac in facilitating the achievement of a highly-saturated or supersaturated residual phase.
Attempts to use diclofenac acid in water-ethanol and glycerol-propylene glycol mixtures have been made, based on a concentration of diclofenac acid between 2.5 and 5% by weight of the formulation, it having been calculated that such a dose should deliver an effective but essentially non-systemic regional amount assuming a product application rate of 2.5 mg/cm2/hour. However, since the saturated solubility of diclofenac acid is only 5% w/w even in pure ethanol and also since the saturated solubility in propylene glycol is relatively high, for example compared with glycerol, at around 1% w/w, it is apparent that only low degrees of super-saturation are achievable unless low percentages of propylene glycol are used. Although higher alcohols, for example propanol or iso-propanol, may be used as partial or total replacement for ethanol, it has been found that the respective saturated solubilities for diclofenac acid are in the region of 3-4% and thus are less than in ethanol.
Carrara (US2005/0244522) describes the use of natural (plant derived) skin permeation enhancers in combination with a diethylene glycol ether and, optionally, propylene glycol to deliver a range of drugs including diclofenac diethyl ammonium in cream form. Diclofenac in vitro penetration is approximately twice that of Voltarol gel. Bauer (EP1588697) describes acrylate hydrogels containing an oxyethylene or oxypropylene emulsified lipophilic phase optionally containing propylene glycol and isopropyl myristate to deliver a range of drugs including diclofenac acid and lysine salt in cream form. WO2010/087947 discloses an oily solution of diclofenac in a range of organic solvents and an emollient, for example an oil, a fatty acid or ester, together with antioxidants, surfactants and the like. WO93/00873 describes an aqueous gel for topical application of diclofenac, the gel containing water, low molecular weight alcohols or glycols and ether alcohols and fatty alcohol esters to enhance transdermal flux. US2007/0280972 describes a gel composition including volatile and non-volatile solvents and a gelling agent whereby, on application to the skin, the volatile solvent evaporates and the gelling agent forms a solid gel layer removable by peeling away or washing. Davis (WO 2008/110741) describes a composition for topical application of an NSAID, the composition comprising a solution or suspension of the NSAID as active ingredient in a carrier system comprising a polyhydric alcohol, a glycol ether and an ester of a higher fatty acid, the carrier system being present as a single phase at ambient temperatures and generally including a lower alcohol diluent, water being essentially absent from the carrier system.
In designing topical formulations for enhanced skin penetration of NSAIDS, efforts have hitherto been principally directed at increasing the solubility of the NSAID in the composition as a whole, that is, before application to the skin. However, where the composition contains volatile solvents, the solvents evaporate on application of the composition to the skin and, it is now realised, the flux is dependent not so much on the absolute concentration of the NSAID in the composition as a whole or even in the residual, non-volatile, phase but more on the degree of saturation of the NSAID in the residual phase. In contrast to the goals hitherto pursued, therefore, it is important to employ a residual phase solvent or solvent blend which has a relatively low solvating power for the NSAID, such that the saturated concentration is relatively low and in consequence the concentration of the NSAID in the residual phase is more likely to achieve saturation or even super-saturation as the volatile ingredients evaporate, thus optimising NSAID flux and driving skin penetration. It is also desirable for the NSAID to be lipid-soluble, to enable or enhance penetration of the stratum corneum.
The compositions disclosed in WO2008/110741, referred to above, are essentially anhydrous, it having been thought that the presence of water militated against a single-phase system and, thus, inhibited skin penetration. Water would, it was believed, act (if present) as a volatile solvent, evaporating from the skin on application thereto of the composition and thus having no effect on the composition or penetration properties of the residual phase.
It has now been realised that, contrary to previous understanding concerning the compositions described in WO2008/110741, water forms an equilibrium mixture with the polyhydric alcohol and thus is not subject to total evaporation on application of the composition to the skin. Therefore, instead of acting as a volatile solvent, water is partially retained by the polyhydric alcohol and thus remains as a component of the residual phase. In conjunction with the polyhydric alcohol, water forms a miscible co-solvent reducing the saturated concentration of the NSAID and enhancing its flux in the residual phase. Contrary to the previously-held understanding, therefore, water is of assistance in increasing flux (and, thus, skin penetration) in (and from) the residual phase.
In the compositions described in WO2008/110741, the polyhydric alcohol, preferably a glycol, renders the active ingredient soluble in the stratum corneum barrier and also increases the solubility of the ester. The ester, preferably a polar lipid, has the effect of increasing diffusivity or transport rate through the stratum corneum barrier. However, the polyhydric alcohol and ester are immiscible in the compositions as described and thus do not form a homogeneous, single-phase carrier system for the active ingredient. The glycol ether is included as a co-solvent and has a polarity between that of the polyhydric alcohol and the ester and is present in an amount at least sufficient to solubilise the other two components and provide a homogeneous, single-phase carrier system. The compositions as described contain (based on the residual phase) at least 2% of ester, in order to effectively increase diffusivity through the stratum corneum and thus requiring concentrations, for example from 30-50% or more of glycol ether solvent to achieve solubilisation. However, the glycol ether is also an excellent solvent for diclofenac and thus reduces the degree of saturation of diclofenac in the carrier system. For this reason, and also to allay any concerns relating to skin irritation or allergic dermatitis following repeated or prolonged exposure to such compositions, it may be considered desirable to reduce the concentration of glycol ether solvent.